Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 6190 nt | 400–1842 |
| NM_001754.4 | RefSeq Select | 5967 nt | 191–1633 |
| NM_001754.5 | MANE Select | 5971 nt | 195–1637 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
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COSMIC Somatic Evidence
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Functional Impact & Domains
Functional Domain
The RUNX1 Q185Sfs*34 variant is a truncating mutation in the RUNX1 gene, a known tumor suppressor involved in hematopoietic differentiation. Functional evidence indicates that truncating mutations in RUNX1 inhibit its function, which is associated with predisposition to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes. This suggests a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 43 bp |
| Donor Loss (DL) | 0.01 | 152 bp |
| Acceptor Gain (AG) | 0.0 | -5 bp |
| Donor Gain (DG) | 0.0 | 455 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines for RUNX1, the rule for PVS1 is: 'Very Strong Strength: Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.' The evidence for this variant shows it is a truncating frameshift (c.529_551dup, p.Q185Sfs*34) in a gene where loss of function is a known mechanism and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because it results in loss of function consistent with the VCEP decision tree.
PS1 (Not Applied)
According to VCEP guidelines for RUNX1, PS1 pertains to the same amino acid change as a previously established pathogenic variant. This variant is a frameshift, not an identical amino acid substitution. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines for RUNX1, PS2 requires proven de novo occurrences with parental testing. No parental testing data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for RUNX1, PS3 is not applicable if the variant meets PVS1. Although functional studies show a damaging effect, PS3 cannot be applied when PVS1 is already met. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines for RUNX1, PS4 requires case‐level evidence (number of probands). No case‐level data are provided. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines for RUNX1, PM1 addresses missense or in‐frame variants affecting specific residues in the RHD. This variant is a frameshift truncation. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for RUNX1, PM2 has Supporting strength: 'Variant must be completely absent from all population databases.' The evidence shows this variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 pertains to detection in trans with a pathogenic variant in recessive disorders. No trans configuration data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 addresses in-frame insertions/deletions. This is a frameshift leading to truncation. Therefore, PM4 is not applied.
PM5 (Supporting)
According to VCEP guidelines for RUNX1, 'PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4)'. This variant is a frameshift at c.529, downstream of c.98. Therefore, PM5 is applied at Supporting strength.
PM6 (Not Applied)
According to VCEP guidelines for RUNX1, PM6 provides evidence for assumed de novo cases. No such data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines for RUNX1, PP1 requires segregation data. No family segregation data are provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 addresses missense variants in genes with low benign missense variation. This variant is a frameshift. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 uses computational predictive data for missense, synonymous, or intronic variants. This frameshift variant has negligible splicing impact but PP3 does not apply to frameshifts. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires detailed phenotypic specificity. No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires a reputable source’s pathogenic assertion. The variant is not reported in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 requires allele frequency ≥0.1%. This variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, BS1 requires allele frequency between 0.015% and 0.1%. This variant is not observed in controls. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 requires observation in healthy adult controls. No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for RUNX1, BS3 addresses normal functional studies. Functional data demonstrate damaging effect. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires non-segregation in unaffected individuals. No such data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 pertains to missense variants in genes where loss of function is the disease mechanism. This variant is a loss-of-function frameshift. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 requires observation in trans or cis with another pathogenic variant. No such data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 addresses in-frame indels in repetitive regions. This is a frameshift duplication not in a repeat region. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, BP4 uses computational benign predictions for missense/synonymous/intronic variants. This is a frameshift. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 addresses variants found in trans with a pathogenic variant in a fully penetrant dominant disorder. No such data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires a reputable source’s benign assertion. No such assertions exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous variants. This is a frameshift. Therefore, BP7 is not applied.